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1-aminobenzotriazole modulates oral drug pharmacokinetics through cytochrome P450 inhibition and delay of gastric emptying in rats

Stringer, Rowan and Weber, Eckhard and Tigani, Bruno and Lavan, Paul and Stephen, Medhurst and Sohal, Bindi (2014) 1-aminobenzotriazole modulates oral drug pharmacokinetics through cytochrome P450 inhibition and delay of gastric emptying in rats. Drug Metabolism and Disposition, 42 (7). pp. 1117-1124. ISSN 1521-009X

Abstract

The simultaneous effect of the cytochrome P450 inhibitor 1-aminobenzotriazole (ABT) on inhibition of in vivo metabolism and gastric emptying was evaluated with the test compound NVS308, a novel CRF1 antagonist with low water solubility, and the reference compound midazolam with high water solubility in rats. Pre-treatment of rats with 100 mg/kg oral. ABT administered 2 hours prior to a semi-solid caloric test meal, markedly delayed gastric emptying. ABT increased stomach weights by 2-fold, this is likely to be attributed to a pro-secretory effect because stomach concentrations of bilirubin were comparable in ABT and control groups. ABT administration decreased the initial systemic exposure of orally administered NVS308 and increased Tmax 40-fold, suggesting gastric retention and delayed oral absorption. ABT increased the initial systemic exposure of midazolam, however for orally (but not subcutaneously) administered midazolam, extensive variability in plasma-concentration time profiles was apparent. Careful selection of administration routes is recommended for ABT use in vivo, variable oral absorption of co-administered compounds can be expected due to a disturbance of gastrointestinal transit.

Item Type: Article
Keywords: Aminobenzotriazole, pharmacokinetic, cytochrome P450, drug metabolism, gastric emptying
Date Deposited: 13 Oct 2015 13:13
Last Modified: 13 Oct 2015 13:13
URI: https://oak.novartis.com/id/eprint/9326

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